This application nNOS-PSD95 inhibitors as novel treatments for TBI addresses the critical need for an efficacious treatment for traumatic brain injury (TBI). TBI is the leading cause of death and disability in the most active population (<45 years of age) in the United States. Unfortunately, no effective pharmaceutical interventions have been developed. Thus, there is a critical need to understand the molecular mechanisms underlying functional deficits after TBI as well as to translate this knowledge into the development of new TBI treatments. In TBI, activation of the NMDA glutamate receptor (NMDAR) stimulates the enzyme neuronal nitric oxide synthase (nNOS) and, ultimately, increases the signaling molecule nitric oxide (NO). Postsynaptic density protein (PSD95) is necessary to position nNOS close to the NMDAR and is therefore required for NMDAR activation of nNOS. This NMDAR-PSD95-nNOS cascade is implicated in the functional deficits following TBI. Anagin, an Indiana-based small business, and its research partners at Indiana University School of Medicine have preliminary results suggesting that a small molecule inhibitor of the interaction between nNOS and PSD95 is neuroprotective in a preclinical model of TBI. The specific aim for this Phase I SBIR program is to test the functional benefits of inhibiting nNOS-PSD95 interaction in a preclinical model of TBI by fully characterizing the dose response and therapeutic window of treatment. If successful, this project will validate a new target and mechanism for intervention for TBI. Future Phase II SBIR studies will determine if the new nNOS-PSD95 inhibitors currently being developed by Anagin are potential drug development candidates for the treatment of TBI.